Kaplan + Sadock's Synopsis of Psychiatry, 11e

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Chapter 1: Neural Sciences

gene, translation of a polypeptide preprohormone encoded by that mRNA, and then posttranslational processing involving proteolytic cleavage of the preprohormone to yield the active neuropeptide. Over the last 25 years the gene structures and biosynthetic pathways of many neuropeptides have been eluci- dated. The gene structure of selected neuropeptides is illustrated in Figure 1.4-11. Neuropeptide genes are generally composed of multiple exons that encode a protein preprohormone. The N- terminus of the preprohormone contains a signal peptide sequence, which guides the growing polypeptide to the rough endoplasmic reticulum (RER) membrane. The single prepro- hormone molecule often contains the sequences of multiple peptides that are subsequently separated by proteolytic cleav- age by specific enzymes. For example, translation of the gene encoding NT yields a preprohormone, which upon enzymatic cleavage produces both NT and neuromedin N. Distribution and Regulation Although many neuropeptides were originally isolated from pituitary and peripheral tissues, the majority of neuropeptides were subsequently found to be widely distributed through- out the brain. Those peptides involved in regulating pituitary secretion are concentrated in the hypothalamus. Hypothalamic releasing and inhibiting factors are produced in neurosecretory neurons adjacent to the third ventricle that send projections to the median eminence where they contact and release peptide into the hypothalamohypophysial portal circulatory system. Peptides produced in these neurons are often subject to regula- tion by the peripheral hormones that they regulate. For example, thyrotropin-releasing hormone (TRH) regulates the secretion of thyroid hormones, and thyroid hormones negatively feedback on TRH gene expression. However, neuropeptide-expressing neurons and their projections are found in many other brain regions, including limbic structures, midbrain, hindbrain, and spinal cord. Neuropeptide Signaling Neuropeptides may act as neurotransmitters, neuromodulators, or neurohormones. Neurotransmitters are typically released from axonal terminals into a synapse where they change the postsynaptic membrane potential, either depolarizing or hyper- polarizing the cell. For classical neurotransmitters, this often involves direct modulation of voltage-gated ion channels. In contrast, neuromodulators and neurohormones do not directly affect the firing of the target cell itself but may alter the response of the cell to other neurotransmitters through the modulation of second messenger pathways. Neuropeptide release is not restricted to synapses or axon terminals but may occur through- out the axon or even from dendrites. The cellular signaling of neuropeptides is mediated by spe- cific neuropeptide receptors. Thus understanding neuropeptide receptor function is essential for understanding neuropeptide biology. Neuropeptide receptors have undergone the same pro- cess of discovery and characterization that receptors for other neurotransmitters have enjoyed. Most neuropeptide receptors are G-protein-coupled, seven-transmembrane domain recep- tors belonging to the same family of proteins as the monoamine receptors.

leading ultimately to the cloning and characterization of the genes encoding them. Characterization of the gene structure of peptides and their receptors has provided insight into the molecular regulation of these systems, and their chromosomal localization is useful in genetic studies examining the potential roles of these genes in psychiatric disorders. Structural charac- terization permits the production of immunological and molec- ular probes that are useful in determining peptide distribution and regulation in the brain. Quantitative radioimmunoassays on microdissected brain regions or immunocytochemistry on brain sections are typically used to localize the distribution of pep- tide within the brain. Both techniques use specific antibodies generated against the neuropeptide to detect the presence of the peptide. Immunocytochemistry allows researchers to visualize the precise cellular localization of peptide-synthesizing cells as well as their projections throughout the brain, although the technique is generally not quantitative. With molecular probes homologous to the mRNA encoding the peptides or receptor, in situ hybridization can be used to localize and quantify gene expression in brain sections. This is a powerful technique for examining the molecular regulation of neuropeptide synthesis with precise neuroanatomical resolution, which is impossible for other classes of nonpeptide neurotransmitters that are not derived directly from the translation of mRNAs, such as dopa- mine, serotonin, and norepinephrine. Generally, the behavioral effects of neuropeptides are initially inves- tigated by infusions of the peptide directly into the brain. Unlike many nonpeptide neurotransmitters, most neuropeptides do not penetrate the blood–brain barrier in amounts sufficient enough to produce CNS effects. Furthermore, serum and tissue enzymes tend to degrade the peptides before they reach their target sites. The degradation is usually the result of the cleavage of specific amino acid sequences targeted by a specific peptidase designed for that purpose. Thus, intracerebroven- tricular (ICV) or site-specific infusions of peptide in animal models are generally required to probe for behavioral effects of peptides. However, there are some examples of delivery of neuropeptides via intranasal infusions in human subjects, which in some cases has been shown to permit access of the peptide to the brain. One of the greatest impediments for exploring the roles and poten- tial therapeutic values of neuropeptides is the inability of the peptides or their agonists/antagonists to penetrate the blood–brain barrier. Thus the behavioral effects of most peptides in humans are largely uninves- tigated, with the exception of a few studies utilizing intranasal deliv- ery. However, in some instances small-molecule, nonpeptide agonists/ antagonists have been developed that can be administered peripherally and permeate the blood–brain barrier in sufficient quantities to affect receptor activation. The use of pretreatment and posttreatment CSF samples or of samples obtained during the active disease state versus when the patient is in remission addresses some of the serious limita- tions in study design. For such progressive diseases as schizo- phrenia or Alzheimer’s disease, serial CSF samples may be a valuable indicator of disease progression or response to treat- ment. Even with these constraints, significant progress has been made in describing the effects of various psychiatric disease states on neuropeptide systems in the CNS. Biosynthesis Unlike other neurotransmitters, the biosynthesis of a neuro- peptide involves the transcription of an mRNA from a specific